Tetrahydropyrrolo{8 1,2-a{9 pyrazine-1(2H),4(3H)-diones

ABSTRACT

6,7,8,8A-Tetrahydropyrrolo(1,2-a)pyrazine-1(2H)-4(3H)-diones of the formula   where R is hydrogen, lower alkyl, a phenyl or a benzyl radical, R1 is hydrogen or a lower alkyl radical, R2 is (a) a COR3 radical where R3 is selected from the group hydroxy, lower alkoxy, monoand di-lower alkylamino-lower alkoxy, amino, mono- and di-lower alkylamino, mono- and di-lower alkylamino-lower alkylamino, a phenylamino, hydroxyamino, a morpholine, pyrrolidine, piperidine, and piperazine ring which ring may also have 1 or 2 lower alkyl substituents; (b) a CH2R4 radical where R4 is selected from the group hydroxy, carboxy, carbo(lower alkoxy), lower acyloxy and carbamyloxy. The compounds of the invention are useful as C.N.S. depressants and in particular as tranquilizing agents.

United States Patent [191 Fontanella et a1.

[ Nov. 18, 1975 TETRAHYDROPYRROLO[1,2-

A ]PYRAZINE- 1 2H ),4(3H )-DIONES [75] Inventors: Luigi Fontanella;Luigi Mariani,

both of Milan, Italy 30 Foreign Application Priority Data Nov. 3, 1972Italy 31276/72 52 US. Cl .250 250 BC; 260/247.2 A;

OTHER PUBLICATIONS 'Lucente, et a1. Chemical Abstract 75: 64266x (1971).

Primary ExaminerRichard J. Gallagher Attorney, Agent, or Firm-TheodorePost; Kenneth Bjork [5 7 ABSTRACT 6,7,8,8a-Tetrahydropyri'olo[ 1,2-a]pyrazine- 1 (2H)- 4(3l-l)-diones of the formula where R ishydrogen, lower alkyl, a phenyl or a benzyl radical, R is hydrogen or alower alkyl radical, R is (a) a COR radical where R, is selected fromthe group hydroxy, lower alkoxy, monoand di-lower alkylamino-loweralkoxy, amino, monoand di-lower alkylamino, monoand di-loweralkylamino-lower alkylamino, a phenylamino, hydroxyamino, a morpholine,pyrrolidine, piperidine, and piperazine ring which ring may also have 1or 2 lower alkyl substituents; (b) a CI-I R radical where R, is selectedfrom the group hydroxy, carboxy, carbo(lower alkoxy), lower acyloxy andcarbamyloxy. The compounds of the invention are useful as C.N.S.depressants and in particular as tranquilizing agents.

3 Claims, No Drawings TETRAHYDROPYRROLO[ 1 ,2-A1PYRAZINE-l(2H),4(3H)-DIONES SUMMARY OF THE INVENTION This invention relates tonew 6,7,8,8a-tetrahydropyrrolo[ l ,2-a1pyrazinel (2H),4(3H)-dionesrepresented by the formula wherein R represents a hydrogen, lower alkyl,a phenyl or a benzyl radical, R represents a hydrogen or lower alkylradical, R represents (a) a COR radical wherein R is selected from thegroup of hydroxy, lower alkoxy, mono-and di-lower alkylamino-loweralkoxy, amino, monoand di-lower alkyl amino, monoand di-loweralkylamino-lower alkylamino, a phenylamino, hydroxyamino, a morpholine,pyrrolidine, piperidine and piperazine ring which ring may have 1 or 2lower alkyl substituents; (b) a CH R radical wherein R is selected fromthe group hydroxy, carboxy, carbo(lower alkoxy), lower acyloxy andcarbamyloxy.

In the specification and claims, the following terms by themselves andin compound terms have the following meanings: lower alkyl and loweralkoxy designate alkyl and alkoxy groups containing from 1 to 4 carbonatoms; lower acyloxy designates an acyloxy lower alkyl substituentgroups.

The compounds of this invention from which the whole series of inventivecompounds is derived are those of formula (I) wherein R represents a CORradical wherein R represents lower alkoxy, The ester function maythen beeasily converted to carboxy, car- 'bamyl and all of the othersubstituents mentioned before. A preferred embodiment of the inventioncomprises those lower alkyl esters which are obtained through thefollowing reaction scheme, wherein R and R have the same meanings asgiven above and the term halo" refers to bromo or chloro:

Scheme 1 CO.\ RNH CH-CH,

I I haloOC-CH-R, HN H,

\ halo CH iOOlower allcyl -continued RNH CH CH halo CO CH COOlower alkyl(Ill) CO CH The starting 2-carbamyl-5-carbo(lower alkoxy)pyrrolidinederivatives of formula (II) may be prepared as described by G.Cignarella et al. in Gazz. Chim. Italiana, 92, 1093,0962) by heating,for example, 2,5- dicarbethoxy-pyrrolidine with about one equimolecularproportion of an indicated amine in a high boiling inert organicsolvent. In some instances, the two reactants may be heated togetherwithout any solvent for 3-40 hours at a temperature varying from about150 to about 250C. The 2-carbamyl-5-carbo-(lower alkoxy)pyrrolidinederivatives are generally obtained as cisand transisomeric mixtures. Theintermediates of formula (III) are prepared by reacting compounds offormula (II) with an a-halo-acyl halide in an inert organic solvent suchas, for example, diethyl ether, in the presence of an acid acceptor suchas, for example, triethylamine. The last intramolecular cyclization stepis carried out by heating the compounds of formula (III) in the presenceof a strong base such as, for example, sodium amide. The reactiontemperature may vary from about 20 to about C., and the time of thereaction may range from about 1 to about 20-30 hours.

Another procedure for preparing the esters is based on the followingsteps:

Scheme 2 COOlower alkyl COOlower alkyl -continued R-N CH-CHZ R,CH N CH,

CO CH COOlower alkyl wherein halo, R and R have the same meaning asgiven before. The reaction between a 2,5-dicarbo(lower al-'koxy)-pyrrolidine and an a-halo-acylhalide is carried out essentiallyunder the same conditions as for the preparation of the intermediate(11]) of the process described in Scheme 1. The second step of Scheme 2is carried out by refluxing for 5-25 hours the intermedi- -ate diester(VI) together with an indicated amine in the presence of an acidacceptor. Toluene, xylene and other inert organic solvents areadvantageously used as the reaction solvents and triethylamine, sodiumamide or an excess of the same amine, RNl-l may be used as acidacceptors. To complete the cyclization reaction, in some instances theoily residue obtained after evaporation of the organic solvent is heatedfor 1-5 hours at 150-260C. The esters of formula (IV) may be convertedthrough alkaline hydrolysis to the corresponding acids which in turn areconverted to the amide by treat ment withethyl chlorocarbonate inthepresence of triethylamine followed by reaction with an indicated amine.The latter procedure may also be followed to obtain esters from thecorresponding acids if an alcohol is employed instead of an amine. Analternative method for preparing amides or estersfrom the correspondingacid derivatives consists in the transformation of the acid function toacarbonyl halide with a halogenating reagent such as SOCI PCl POCl andthe like, followed by reaction with an amine or an alcohol. Theindicated carbonyl halides are also. suitable intermediates forobtaining compounds of formula (I) wherein R represents hydroxymethyl.In this case the reduction reaction is advantageously carried out byemploying an alkali metal borohydride, advantageously sodiumborohydride, as reducing agent. The so-obtained hydroxymethylderivatives are easily transformed to acyloxymethyl compounds with anacylating agent. The compounds of formula (I) wherein R is carbo(loweralkoxy)-methyl, i.e., CH COOlower alkyl, are prepared from thecorresponding compounds of formula (I) where R is a carboxy group viathe Arndt-Eistert method. The resulting ester group may subsequently betransformed to the acid group by alkaline hydrolysis.

The compounds of formula (1) wherein R is a lower alkyl radical possessthree asymmetric centers, i.e., the carbon atoms in positions 3, 6 and8a, and, therefore, eight stereoisomers are theoretically possible. WhenR is hydrogen, the possible stereoisomers are four. Fractionalcrystallization and chromatographic techniques are useful for separatingthe racemates which, in turn, are mixtures of optical isomers(enantiomers). Resolution of racemic mixtures into their optical isomersmay be effected after introduction of a new optically active center.Thus, for instance, in the case of acidic components, salts withoptically active bases or esterification with optically active alcoholsallows separation of the two components. The salts or the esters maysubsequently be reconverted to the original free acid derivatives.

The additional examples and descriptions of utility provide in detailmethods for the manufacture of representative compounds of the inventionand their useful- 4 ness. The symbols a and ,8 are used to identify twodifferent isomers when they are separated from the reaction mixture. Thecompounds of the a series are derived from the isomeric forms of theesters of formula (IV) which are first eluted during the separation bycolumn chromatography.

EXAMPLE 1:

3-Methyl-2-(p-tolyl)-6,7,8,8a-tetrahydro-l-(ZH), 4(3l-l)-dioxopyrrolo[ l,2-a]pyrazine-6-carboxylic acid ethyl ester (oz-isomer) A sodium amidesuspension is prepared by dissolving 1.5 g. of sodium in an excess (750ml.) of liquid Nl-l in the presence of a crystal of Fe(NO and stirringthe mixture to a complete formation of sodium amide. To

this suspension, 25.5 g. of 1-(2-bromopropionyl)-5-(p-.

EXAMPLE 2:

2-Benzyl-3-ethyl-6,7,8,8a-tetrahydro-l (2H),- 4( 3l-l)-dioxopyrrolo[ l,2-a]pyrazine-6-carboxylic acid ethyl ester (oz-isomer and B-isomer) Asodium amide suspension is prepared by dissolving 3.5 g. of sodium in anexcess (1500 ml.) of liquid Nl-l To the amide suspension at about -C.,63 g. of 5- benzylcarba myll 2-bromobutyryl )py rrolidine-Z-carboxylicacid ethyl ester is added in small portions under stirring. Then 1000ml. of anhydrous diethyl ether is added and stirring is continued tocomplete evaporation of the excess ammonia. The mixture is then refluxedfor about 3 hours and after cooling is washed with water to dissolve theinorganic salts. The organic layer is separated, dried and evaporated togive 48 g. of an oily residue which is dissolved in benzene andchromatographed through a silica-gel column by using benzol:diethylether 8:2 as the eluent. The first fractions which contain someimpurities are discarded while the intermediate fractions afterevaporation give 32 g. of

the a-isomer boilingat 210C./0.5 mm Hg. and the last fractions give 4.4g. of the B-isomer melting at l35-139 C. after crystallization fromdiisopropyl ether.

EXAMPLE 3:

3-Methyl-6,7,8 ,8a-tetrahydrol (2H),4( 3H)-dioxapyrrolo[1,2-a]pyrazine-6-carboxylic acid ethyl ester ration ofthe chloroform solution, 20 g. of the title compound is obtained whichmelts at 182-184C.

EXAMPLE 4:

3-Methyl-2-(p-tolyl)-6,7,8,8a-tetrahydro-1(2H),4(3H)-dioxopyrrolo[1,2-a]pyrazine-6-carboxylic acid ethyl ester(oz-isomer and B-isomer) To a solution of 70 g.l-(2-bromopropionyl)-2,5- dicarbethoxypyrrolidine in 650 m1. of toluene,24 g. of p-toluidine and 24 g. of triethylamine are added and, afterintroduction of a catalytic amount of sodium (0.1 g.), the mixture isrefluxed for 18 hours. After cooling, the triethylamine hydrobromide isfiltered off and the solvent is evaporated. The oily residue is thenheated under a nitrogen atmosphere at 240-250C. The reaction is followedby collecting ethanol which forms during the cyclization process andheating is stopped when the distillate becomes strongly alkaline.The-oily product is then taken up with chloroform and the solution iswashed subsequently with water and aqueous sodium bicarbonate. Afterevaporation of the chloroform solution, the residue is dissolved indiethyl ether and is allowed to stand overnight in a refrigerator. Thesolid which precipitates is recovered by filtration, yielding 20 g. ofthe a-isomer, m.p. 159-160C. The oily residue obtained by evaporation ofthe filtrate is dissolved in benzene and chromatographed through asilica gel column and eluting with benzenezethyl acetate 95:5.Evaporation of the first 40 fractions (each of about 200 ml.) givessmall amounts of by-products and of the aisomer, while evaporation ofthe subsequent 40 fractions gives 5.2 g. of the B-isomer which ispurified by trituration with a mixture of diisopropyl ether and diethylether 50:50; m.p. 100-102C.

EXAMPLE 3-Ethyl-2-(p-methoxyphenyl)-6,7,8,8a-tetrahydro-(2H),4(3H)-dioxopyrrolo[1,2-a]pyrazine-6-carboxylic acid ethyl esterEighteen grams of 1-(2-bromobutyryl)-2,5-dicarbethoxypyrrolidine isrefluxed for 6 hours with g. of

6 p-methoxyaniline in 150 ml. of anhydrous toluene. After cooling, thep-methoxyaniline hydrobromide is filtered off and the filtrate isevaporated to dryness. The oily residue is dissolved in diethyl etherand the organic solution is washed with water and then evaporated. Theresidue is heated for 1 hour at 160C. and then for another hour at 200C.The title product is recovered by distilling at 240C./0.6 mm Hg.; yield13 g.

EXAMPLE 6:

2-(p-Chlorophenyl)-3-ethy1-6,7,8,Sa-tetrahydro- (2H),4( 3H)-dioxopyrrolo[ 1',2-a]pyrazine-6-carboxylic acid ethyl ester Thecompound is prepared according to the procedure of Example 5 from 1-(2-bromobutyryl)-2,5-dicarbethoxy-pyrrolidine and p-chloroaniline; b.p.225-230C./0.6 mm Hg.

EXAMPLE 7 3-Ethyl-2-(p-methylbenzyl)-6,7,8,8a-tetrahydro- (2H),'4(3H)-dioxopyrrolo[ 1,2-a] pyrazine-6-carboxylic acid ethyl ester Amixture of 1-(2-bromobutyryl)-2,5-dicarbethoxypyrrolidine (9.2 g) andp-methylbenzylamine (7 g.) in ml. of anhydrous toluene are refluxedtogether for 6 hours. After cooling, the by-product p-methylbenzylaminehydrobromide is filtered off and the solution is evaporated to dryness.The oily residue is dissolved in diethyl ether, and the solution iswashed with water.

TABLE Ex. -2.5-dicarbethoxypyrrolidine amine 6,7,8,8a-tetrahydro- M.P.C.

N0. 7 1(2H),4(3H)-dioxopyror rolo[1,2-a]pyrazine-6- B.P. C./mm Hg.carboxylic acid ethyl ester 8 1-( 2-bromopropionyl benzylamine2-benzy1-3-methyl- 220-230/0.6

9 1-(2-bromobutyryl)- p-chlorobenzylamine Z-(p-chlorobenzyl)-3-ethyl230/0.5

l0 1-(2-bromohexanoyl)- p-chlorobenzylamine 3-butyl-3-(p-chlorobenzyl)-250/0.6

1 l 1-( 2-bromo-3-methylbu tyryl p-chlorobenzylamine 2-( p-chlorobenzyl)-3-isopropyl 220/0.4

12 l-( 2-bromo-3-methylbu tyryl) p-methoxybenzylamine 3-isopropyl-2-(p-methoxy- 240/05 benzyl 13 1-( 2-bromohexanoyl)- p-methoxybenzylamine3-butyl-2-( p-methoxybenzyl 240/0.4

14 l-(2-bromobutyry1)- p-methoxybenzylamine 3-ethyl-2-(p-methoxybenzyl)- 240/0.4

15 l-(2-bromo-4-methylvaleryl)- p-chlorobenzylamine2-(p-chlorobenzyl)-3-isobutyl 235/05 16 l-(2-bromo-4-methylvaleryl)-benzylamine 2-benzyl-3-isobutyl 230235/0.5 l7l-(2-bromo-4-methylvaleryl)- p-methoxybenzylamine3-isobutyl-2-(p-methoxybenzyl)- 240/05 18 1-(2-bromo-3-methylbutyryl)-p-methylbenzylamine 3-isopropyl-2(p-rnethylbenzyl)- 220/05 19l-(2-bromo-4-methylvaleryl)- p-methylbenzylamine3-isobutyl-2-(p-methylbenzyl)- 220225/0.5 20 1-( 2-bromohexanoyl)-3,4-dimethylbenzylamine 3-butyl-2-( 3,4-dimethylbenzyl)- 245250/0.5 21l-(2-bromohexanoyl)- p-methylbenzylamine 3-butyl-2-(p-methylbenzyl)-230/0.4 22 1-(2-bromohexanoyl)- benzylamine 2-benzy1-3-butyl-215-230/0.3 23 1-(2-bromohexanoyl)- 3,4-dimethylbenzylamine3-ethy1-3-(3,4-dimethylbenzyl)- 240-250/0.6 24 1(2-bromo-3-methylbutyryl)- benzylamine 2-benzyl-3-isopropyl- 2l0215/0.525 1-(2-bromopropionyl)- o-anisidine a-3-methyl-2-(o-anisyh- [34-136 261-(2-bromopropiony1)- o-anisidine B-3-methyl-2-(o-anisyl)- 220230/0.6 271-(2-bromopropionyl)- p-anisidine a-3-methyl-2-(p-anisyl)- -142 281-(2-bromopropionyl)- panisidine B-3-methyl-2-(p-anisyl)- 134-135 29l-(2-bromopropionyl)- o-chloroaniline a-3-n-iethyl-2-(o-chlorophenyl)-137-138 30 1-(2-bromopropionyl)- o-chloroanilineB-3-methyl-2-(o-chlorophenyl)- 108 31 1-(2-bromopropiony1)-p-chloroaniline 3-methyl-2-(p-chlorophenyl)- 144 9 63. 2-(m-Anisyl)-3-methyl-6,7 ,8 ,8a-tetrahydro- 1(2l-l 4( 3H )-dioxopyrrolo[ 1,2-a]pyrazine-6-carboxylic acid, m.p. ll3115C.

The corresponding ethyl ester is obtained in a 72% yield, pursuant tothe procedure of Example 1, but using as the starting material1-(2-bromohexanoyl)-5- butylcarbamyl-pyrrolidine-Z-carboxylic acid ethyles- 64. Z-(o-Chlorophenyl)-3-methyl-6,7,8,8a-tetrahyter. The crude esteris hydrolyzed with l N potassium dro-l(2l-l),- hydroxide in ethanolsolution. The title compound so 4(3l-l)-dioxopyrrolo[ 1,2-a]pyrazine-6-carboxylic obtained melts at l63166C. acid (oz-isomer),m.p. l96l99C.

65. 2-(o-Chlorophenyl)-3-methyl-6,7,8,8a-tetrahy- EXAMPLE dro-l (2H 1O2-Benzyl-N,N,3-triethyl-6,7,8 ,Sa-tetrahydro- 4( 3H )-dioxopyrrol0[ l,2-a]pyrazine-6-carboxylicl(2H),4(3H)-dioxopyrrolo[1,2-a]pyrazine-6-carboxaacid (B-isomer), m.p.140C. mide 66. 3-Methyl-2-(m-tolyl)-6,7,8,8a-tetrahydro- T l f 4 8 f th16 7 8 8 l(2H),4(3H)-dioxopyrrolo[1,2-a]pyrazine-6-carg ijf f O o enzy ey a boxylic acid (at-isomer), m.p. '191l92C.

67 3 Methyl 2 (m mlyl) 6 7 8 8a tetrahydm(2H),4(3H)-dloxopyrrolo[1,2-a]pyrazlne-6-carboxyllc 1(2H) 4(3H)dioxopyrmlo[l 2 a]pyraZine 6 Car acid and 2.3 g. of trlethylamlne in 150ml. of chloroboxyli acid (B iSOmer) m l87 188C form, 15 ml. of ethylchlorocarbonate in 10 ml. of chlo- 68 i 7 8 8a tetr'ahydr0 roform areadded at 0C. After stirring for minutes, 1(2H)4(3H) dioxopyrrolo[l,zalpyrazine 6 car 20 1.3 ml. of dlethylamlne m 10 ml. of chloroform isboxylic acid (wisomer) m p 235 236C added. The mixture is refluxed for15 minutes and after 8 8a tetr'ahydm cooling the organic solution iswashed with water. M2) 4 (3H) dioxopyrrolo[l Evaporation of thechloroform gives a residue which is boxyli acid (B iSOmer) m p l8O l83Ctriturated with diisopropyl ether to give the titular o o 70.2-(o-Anisyl)-3-methyl-6,7,8,8a-tetrahydroproduct yleld 160 highlEXAMPLES 78-89:

ioxo rroo 1,2-a 'n -6- bo l' i gz 43x633 e car Xy Pursuant to the methoddescribed ln the previous ex.

71 2 (o AniSyl) 3 methyl 6,78,8a tetrahydm ample and by starting withthe corresponding 6-car- 10H) 4 (3H) dioxopyrroio[l z a]pyrazine 6 carboxylic acid and the amine or alcohol indicated in colboxylic acid(8480mm), m p 103040500 umn (A) of the Table below, the following amidecom- 72. 2-(m-Chlorophenyl)-3-methyl-6,7,8,8a-tetrahy- Pounds arePrepared- EXAMPLE 76:

2,3-Dibutyl-6,7,8,8a-tetrahydro-l (2H),4( 3H)-dioxopyrrolo[1,2-a]pyrazine-6-carboxylic acid EXAMPLE 9():

2-Benzyl-3-ethyl-6,7,8,8a-tetrahydro-l(2H),4(3H)- dioxopyrrolo[ 1,2-a]pyrazine-6-methanol A mixture of2-benzyl-3-ethyl-6,7,8,8a-tetrahydro- (2H),4(3H)-dioxopyrrolo[l,2-a]pyrazine-6-carboxylic acid (6.7 g.), 10 ml. of SOC 1 and two dropsof dimethylformamide in 100 ml. of chloroform is allowed to standovernight. The solvent is evaporated in vacuo and the oily residue isdissolved in dioxane ml.). To the resulting solution of the acidchloride, 5 g. of sodium borohydride in ml. of dioxane is added and thesolution is refluxed for 3 hours. Water (15 ml.) is added to thereaction mixture which is stirred for 30 minutes, then extracted severaltimes with diethyl ether. Evaporation of the ether extracts gives 7.8 g.of the title product which is purified by distillation at 220230C./0.5mm Hg., m.p. 9395C.

11 EXAMPLE 91;

3-Methyl-2-(p-tolyl)-6,7 ,8,8a-tetrahydro-l (2H),- 4( 3H)-dioxopyrrolo[l ,2-a]pyrazine-6-methanol The title compound is obtained from thecorresponding 6-carboxylic acid by following the same procedure as inthe previous example; m.p. l22l24C.

EXAMPLE 92:

2-Benzyl-3-ethyl-6,7,8,8a-tetrahydro-l(2H),- 4( 3H )-dioxopyrrolo[ 1,2-a]pyrazine-6-methanol acetate To 4.1 g. of2-benzyl-3-ethyl-6,7,8,8a-tetrahydro- 1 (2H ,4( 3H )-dioxopyrrolo[ l,2-a]pyrazine-6-methanol and 7 g. of triethylamine in 50 ml. of benzene,a solution of 3.8 g. of acetyl chloride in 10 ml. of benzene is added atll5C. After refluxing for 3 hours and filtering off the by-producttriethylamine hydrochloride, the solvent is evaporated and the oilyresidue is purified by chromatographing through a silica gel column andeluting with benzene:acetone 95:5 and distilled at 230C./O.6 mm Hg.,yield 2 g. of titular product.

EXAMPLE 93:

3-Methyl-2-(p-tolyl)-6,7,8,8a-tetrahydro-1(2H),- 4( 3H )-dioxopyrrolo[ l,2-a]pyrazine-6-methanol acetate The title compound is prepared from thecorresponding 6-carboxylic acid by following the procedure of theprevious example, m.p. l26l28C.

EXAMPLE 94:

2-Benzyl-3-ethyl-6,7,8 ,Sa-tetrahydro-l (2H),- 4(3H )-dioxopyrrolo[ l,2-a]pyrazine-6-acetic acid ethyl ester Ten grams of2-benzyl-3-ethyl-6,7,8,8a-tetrahydro- (2H),4(3H)-dioxopyrrolo[ l,2-alpyrazine-6-carboxylic acid is transformed into the correspondingcarbonyl chloride pursuant to the procedure described in the first partof Example 90, then it is dissolved in 60 ml. of dichloromethane and 90ml. of anhydrous diethyl ether. To this solution, a diethyl ethersolution containing 2.5% of diazomethane is added dropwise at about 0C.until a persistent yellow color develops. The resulting mixture isstirred for one hour, then is allowed to stand overnight in arefrigerator. Evaporation of the solvent gives 13 g. of an oily residuewhich is dissolved in 100 ml. of dry ethanol. To this solution, 3 g. ofsilver benzoate in 27 ml. of triethylamine is added successively inthree portions and the mixture is refluxed for 2 hours. After cooling,the reaction mixture is filtered and the filtrate is evaporated todryness. The residue is dissolved in chloroform, washed with aqueoussodium carbonate and water. The solvent is then evaporated and theresidue is purified by distilling at 240245C./0.6 mm Hg, to give thetitular product.

EXAMPLE 95 and 96:

By starting with the respective 6-carboxylic acids and proceeding as inExample 94, the following compounds are prepared:

95. 2-Benzyl-3-butyl-6,7,8,8a-tetrahydrol(2H),4( 3H )-dioxopyrrolo[ l,2-a]pyrazine-6- acetic acid ethyl ester, m.p. 220-230C./0.6 mm Hg.

96. 3-Butyl-2-(3,4-dimethylbenzyl)-6,7,8,8a-tetrahy- LII 12(2H),4(3H)-dioxopyrrolo[ l ,2-a]pyrazine-6-acetic acid ethyl ester, m.p.240-250fC./0.6 mm Hg.

EXAMPLE 97:

3-Methyl-2-(p-tolyl)-6,7,8,8a-tetrahydro-l (2H),- 4(3H )-dioxopyrrolo[l,2-a1pyrazine-6-methanol carbamate To 4 grams of3-methyl-2-(p-tolyl)-6,7,8,8a-tetrahyl(2H),4(3H)-dioxapyrrolo[ l,2-a]pyrazine-6-methanol in 25 ml. of trichloroethylene a solution of1.8 g. of phosgene in 50 ml. of trichloroethylene is added at 02C. Themixture is then refluxed for 2 hours and dry ammonia is then bubbledinto the reaction vessel. The product which precipitates is washed withwater and crystallized from ethanol, yield 3.8 g. of titular product,m.p. l74l76C.

EXAMPLE 98:

1-( 2-Bromopropionyl )-5 -(p-tolylcarbamyl )pyrrolidine-Z-carboxylicacid ethyl ester To a solution of 45.3 g. of5-(p-tolylcarbamyl)-pyrrolidine-Z-carboxylic acid ethyl ester and 19.7g. of triethylamine in 750 ml. of diethyl ether 31 g. of 2-bromopropionyl chloride in 60 ml. of diethyl ether is added at 05C. Themixture is then refluxed for 1 hour and, after cooling, is washedsuccessively with water, dilute HCl and again with water. Evaporation ofthe organic layer gives 26 g. of the titular product, melting atll4116C. By operating according to the procedure of this example, thefollowing compounds are prepared:

l-( 2-Bromohexanoyl )-5-butylcarbamyl-pyrrolidine- 2-carboxylic acidethyl ester (oily). 5-Benzylcarbamyl-l 2-bromobutyryl)-pyrrolidine-2-carboxylic acid ethyl ester, m.p. -87C.

By using 2,5-(dicarbethoxy)pyrrolidine and an indicated 2-bromoalkanoylchloride as the starting compounds and by operating essentially asdescribed above, the following 2,5-dicarbethoxypyrrolidine derivativesare obtained: l-(2-bromoacetyl)-2,5-dicarbethoxypyrrolidinel-(2-bromopropinoyl)-2,5-dicarbethoxypyrrolidine (oily)l-(2-bromobutyryl)-2,5-dicarbethoxypyrrolidine (oily) l2-bromo-3-methylbutyryl )-2 ,S-dicarbethoxypyrrolidine (oily)l-(2-bromo-hexanoyl)-2,5-dicarbethoxypyrrolidine (oily) 1-(2-bromo-4-methyl-valeryl)-2,5-dicarbethoxypyrrolidine (oily).

2 ,5-Dicarbethoxypyrrolidine and the esters of5-carbamylpyrrolidine-2-carboxylic acids are prepared according to themethods described by Cignarella et al. in J. Org. Chem. 26, 1500, (1961)and by cignarella et al. in Gazzetta Chimica ltaliana 92, -l093, (1962).

The depressant activity of the inventive compounds on the centralnervous system, CNS. activity, is evidenced by testing the compounds inmice according to the Irwin method. The tranquilizing and anxiolyticactivity is evaluated on the basis of the secondary conditioned responsein rats. The sedative activity is also evidenced in cats, dogs andmonkeys. The effective dosage of representative compounds tested inanimals ranges from about 10 mg./kg. to about 200 mg/kg. i.p. Thetoxicity of the new compounds is very low. Representative of suchactivity, the compound 3-methyl-2- (p-tolyl)-6,7,8,8a-tetrahydro-l(2H),4( 3H)-dioxapyrrolo [l,2-a]pyrazine-6-carboxylic acid ethyl ester(aisomer) showed the following ED values for the following parameters ofthe Irwin test which are related to a sedative and hypnotic effect:

Parameters ED, in mice Righting reflex 30 mg./kg. i.p. lmpairment ofmotor coordination 60 mgjkg. ip. Spontaneous activity 60 mg./kg. i.p.Minimal hypnotic dose 200 mg/kg. iipv i.p. in mice.

What is claimed is: 1. A compound represented by the formula wherein Rrepresents hydrogen, lower alkyl, phenyl, substituted phenyl having upto 2 substituents selected from lower alkyl, lower alkoxy, fluoro,chloro and bromo, benzyl or substituted benzyl having up to 2substituents selected from lower alkyl, lower alkoxy, fluoro, chloro,and bromo; R represents hydrogen or lower alkyl; R represents (a) CORwherein R is selected from the group consisting of hydroxy, loweralkoxy, monoand di-lower alkylamino-lower alkoxy, amino monoand di-loweralkylamino, monoand dilower alkylamino-lower alkylamino, phenylamino,substituted phenylamino wherein substituted phenyl is as defined above,hydroxyamino and morpholino, pyrrolidino, piperidino and piperazinowhich said hetero groups may be substituted with up to 2 lower alkylgroupsor (b) CH2 R4 wherein R4 is selected from hydroxy, carboxy,carbo(lower alkoxy), l to 4 carbon alkanoyloxy and carbamyloxy. I

2. A compound as claimed in claim 1 wherein R represents phenyl,substituted phenyl, benzyl or substituted benzyl, having the saidsubstituents as defined, R represents hydrogen or lower alkyl, and Rrepresents -COR wherein R represents hydroxy or lower alkoxy.

3. A compound as claimed in claim 2 which is 3-methyl-2-(p-tolyl)-6,7,8,8a-tetrahydro-l (2H ),4( 3Hdioxopyrrolo[l,2-a]pyrazine-6-carboxylic acid (alphaisomer) or its ethylester.

Page 1 of 3 UNITED STATES PATENT AND TRADEMARK OFFICE CER'HFICATE 0FCORRECTION PATENTINO- 3,920,660

DATED November 18, 1975 |NV ENTOR(S) Luigi Fontanella; Luigi Mariani Itis certified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Column 5, line 39, at the end of the line, "tetrahydro" should readtetrahydro-l-;

Column 6, line 11, at the end of the line, "tetrahydro" should readtetrahydro-l;

Column 6, line 24, at the end of the line, "tetrahydro" should read-tetrahydrol--;

Column 6, line 37, "EXAMPLES 8-35" should be set off as a new paragraphheading;

Columns 5 and 6, in the Table, fourth heading, first line,

"6,7,8,8atetrahydro-" should read -6,7,8,8a tetrahydro- Columns 5 and 6,in the Table, fourth heading, second line,

"1 (2H) ,4 (3H) -dioxopyr" should read --1 (2H) ,4 (3H)- dioxopyr-Columns 5 and 6, in the Table, under the fourth heading,

Ex. No. 10, "3-butyl-3-(p-chlorobenzyl)" should read3-butyl-2-(pchlorobenzyl) Columns 5 and 6, in the Table, under thefourth heading,

Ex. No. 23, "3-ethyl-3-(3,4dimethylbenzyl)-" should read3ethyl2-(3,4-dimethylbenzyl) Columns 5 and 6, in the Table, fifthheading, line 3, "B.P. C./mm Hg. should read -B.P. C./Irun Hg.--;

Columns 7 and 8, in the Table continued, fourth heading, line 1"6,7,8,8a-tetrahydro" should read -6,7,8,8a-

Page 2 of 3 UNITED STATES PATENT AND TRADEMARK OFFICE QERHFICATE OFCORREQ'HUN PATENT NO. 3,920,660 DATED November 18, 1975 lNVENTOR(5) 3Luigi Fontanella; Luigi Mariani It is certified that error appears inthe above-identified patent and that said Letters Patent are herebycorrected as shown below:

tetrahydro- Columns 7 and 8, in the Table continued, fourth heading,

line 2, "1 (2H) ,4 (3H) dioxopyr" should read 1 (2H) ,4 (3H) dioxopyr-Columns 7 and 8, in the Table continued, fifth heading, line 3, "B.P.C./mm Hg. should read -B.P. C./mm H g,--;

Column 7, Example 38, line 38, "3-Methyl-6,7,8,8a-tetrahydro Ob l(2H),4(3H)-" should read -3Methyl6,7,8,8atetrahydro 1 (2H) ,4 (3H)- .2

Column 8, Example 50, line 25 "rahydro" should read rahydrol;

Column 8, Example 51, line 28, at the end of the line,

"tetrahydro-" should read -tetrahydro-l;

Column 8, Example 56, line 47, before "(2H)" insert -dro-l-;

Column 9, Example 68, line 19, "3-Methyl-2-(otoly)6,7,8,8a tetrahydro-"should read -3-Methyl2- (otolyl)6 ,7,8,8a tetrahydro- Column 9 Example73, line 2, before (2H) insert -drol--; Column 10, .line 14,"tetrahydro" should read --tetrahydro-l-; Column 10, line 33, theformula should read as follows:

CO R-N CH CH R CI l I\ T CH CO CH COX ' Page 3 of 3 UNITED STATES PATENTAND TRADEMARK OFFICE CETIFICATE 0F CORRECTION PATENT NO. 60 DATEDNovember 18, 1975 lN\/ ENTOR(S) Luigi Fontanella; Luigi Mariani It iscertifiedthat error appears in the above-identified patent and that saidLetters Patent are hereby corrected as shown below:

Column 10, first line under the heading of Example 90,

at the end of the line "tetrahydro" should read -tetrahydrol-;

Column 11, line 37, at the end of the line, "tetrahydro" 0 should readtetrahydrol-;

Column ll, line 60, "EXAMPLE 95 and 96:" should read I -EXAMPLES 95 and96:--;

Column 12, line 1, before "(2H)" insert drol-;

Column 12, line 10 before "1 (2H) insert -dro Column 12, line 42, "l-(2-bromopropinoyl)2,5-dicarbethoxypyrrolidine (oily) should read l-(2-bromopropionyl)- 2,5-dicarbethoxypyrrolidine (oily)- and also shouldbe set off as a new paragraph;

Column 12, line 43, "l- (2bromobutyryl)-2,5dicarbethoxypyrrolidine(oily) should be set off as a new paragraph;

Column 12, line 54, "cignarella" should read -Cignarella-;

Column 13, line 14, "rahydro" should read --rahydro-l-;

Column 13, line 18, "does" should read --dose;

Column 14, line 10, "amino" should read -amino,-.

Signed and Sealed this Twentieth Day Of July 1976 [SEAL] O Attest:

RUTH C. MASON C. MARSHALL DANN Arresting Officer Commissioner nj'Patenrsand Trademarks

1. A COMPOUND REPRESENTED BY THE FORMULA
 2. A compound as claimed inclaim 1 wherein R represents phenyl, substituted phenyl, benzyl orsubstituted benzyl, having the said substituents as defined, R1represents hydrogen or lower alkyl, and R2 represents -COR3 wherein R3represents hydroxy or lower alkoxy.
 3. A compound as claimed in claim 2which is3-methyl-2-(p-tolyl)-6,7,8,8a-tetrahydro-1(2H),4(3H)-dioxopyrrolo(1,2-a)pyrazine-6-carboxylic acid (alpha-isomer) or its ethyl ester.